tbuckley/cabot-search huggingface dataset:
Response to Neoadjuvant Targeted Therapy in Operable Head and Neck Cancer Confers Survival Benefit
Authors: Marco A. Mascarella, Tolani F. Olonisakin, Purva Rumde, Varun Vendra, Melonie A. Nance, Seungwon Kim, Mark W. Kubik, Shaum S. Sridharan, Robert L. Ferris, Moon J. Fenton, Daniel R. Clayburgh, James P. Ohr, Sonali C. Joyce, Malabika Sen, James G. Herman, Jennifer R. Grandis, Dan P. Zandberg, Umamaheswar Duvvuri
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Neoadjuvant targeted therapy provides a brief, preoperative window of opportunity that can be exploited to individualize cancer care based on treatment response. We investigated whether response to neoadjuvant therapy during the preoperative window confers survival benefit in patients with operable head and neck squamous cell carcinoma (HNSCC). Patients and Methods: A pooled analysis of treatment-naïve patients with operable HNSCC enrolled in one of three clinical trials from 2009 to 2020 (NCT00779389, NCT01218048, NCT02473731). Neoadjuvant regimens consisted of EGFR inhibitors (n = 83) or anti-ErbB3 antibody therapy (n = 9) within 28 days of surgery. Clinical to pathologic stage migration was compared with disease-free survival (DFS) and overall survival (OS) while adjusting for confounding factors using multivariable Cox regression. Circulating tumor markers validated in other solid tumor models were analyzed. Results: 92 of 118 patients were analyzed; all patients underwent surgery following neoadjuvant therapy. Clinical to pathologic downstaging was more frequent in patients undergoing neoadjuvant targeted therapy compared with control cohort (P = 0.048). Patients with pathologic downstage migration had the highest OS [89.5%; 95% confidence interval (CI), 75.7–100] compared with those with no stage change (58%; 95% CI, 46.2–69.8) or upstage (40%; 95% CI, 9.6–70.4; P = 0.003). Downstage migration remained a positive prognostic factor for OS (HR, 0.22; 95% CI, 0.05–0.90) while adjusting for measured confounders. Downstage migration correlated with decreased circulating tumor markers, SOX17 and TAC1 (P = 0.0078). Conclusions: Brief neoadjuvant therapy achieved pathologic downstaging in a subset of patients and was associated with significantly better DFS and OS as well as decreased circulating methylated SOX17 and TAC1.
Genetic Heterogeneity and Tissue-specific Patterns of Tumors with Multiple<i>PIK3CA</i>Mutations
Authors: Smruthy Sivakumar, Dexter X. Jin, Ruchita Rathod, Jeffrey Ross, Lewis C. Cantley, Maurizio Scaltriti, Jessica W. Chen, Katherine E. Hutchinson, Timothy R. Wilson, Ethan S. Sokol, Neil Vasan
Journal: Clinical Cancer Research (2023)

Abstract Purpose: To comprehensively characterize tissue-specific and molecular subclasses of multiple PIK3CA (multi-PIK3CA) mutations and assess their impact on potential therapeutic outcomes. Experimental Design: We profiled a pan-cancer cohort comprised of 352,392 samples across 66 tumor types using a targeted hybrid capture-based next-generation sequencing panel covering at least 324 cancer-related genes. Molecularly defined subgroups, allelic configuration, clonality, and mutational signatures were identified and tested for association with PI3K inhibitor therapeutic response. Results: Multi-PIK3CA mutations are found in 11% of all PIK3CA-mutant tumors, including 9% of low tumor mutational burden (TMB) PIK3CA-mutant tumors, and are enriched in breast and gynecologic cancers. Multi-PIK3CA mutations are frequently clonal and in cis on the same allele and occur at characteristic positions across tumor types. These mutations tend to be mutually exclusive of mutations in other driver genes, and of genes in the PI3K pathway. Among PIK3CA-mutant tumors with a high TMB, 18% are multi-PIK3CA mutant and often harbor an apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) mutational signature. Despite large differences in specific allele combinations comprising multi-PIK3CA mutant tumors, especially across cancer types, patients with different classes of multi-PIK3CA mutant estrogen receptor–positive, HER2-negative breast cancers respond similarly to PI3K inhibition. Conclusions: Our pan-tumor study provides biological insights into the genetic heterogeneity and tissue specificities of multi-PIK3CA mutations, with potential clinical utility to guide PI3K inhibition strategies.
Association of Habitual Checking Behaviors on Social Media With Longitudinal Functional Brain Development
Authors: Maria T. Maza, Kara A. Fox, Seh-Joo Kwon, Jessica E. Flannery, Kristen A. Lindquist, Mitchell J. Prinstein, Eva H. Telzer
Journal: JAMA Pediatrics (2023)

Social media platforms provide adolescents with unprecedented opportunities for social interactions during a critical developmental period when the brain is especially sensitive to social feedback.
Targeting MCL‐1 and BCL‐2 with polatuzumab vedotin and venetoclax overcomes treatment resistance in R/R non‐Hodgkin lymphoma: Results from preclinical models and a Phase Ib study
Authors: Elisabeth A. Lasater, Dhara N. Amin, Rajat Bannerji, Raghuveer Singh Mali, Kathy Barrett, Ryan N. Rys, Jason Oeh, Eva Lin, Tim Sterne‐Weiler, Ellen Rei Ingalla, MaryAnn Go, Shang‐Fan Yu, Maxwell M. Krem, Chris Arthur, Uwe Hahn, Anna Johnston, Vinit Karur, Nadia Khan, Paula Marlton, Tycel Phillips, Giuseppe Gritti, John F. Seymour, Monica Tani, Sam Yuen, Scott Martin, Matthew T. Chang, Christopher M. Rose, Victoria C. Pham, Andrew G. Polson, YiMeng Chang, Claudia Wever, Nathalie A. Johnson, Yanwen Jiang, Jamie Hirata, Deepak Sampath, Lisa Musick, Christopher R. Flowers, Ingrid E. Wertz
Journal: American Journal of Hematology (2023)

The treatment of patients with relapsed or refractory lymphoid neoplasms represents a significant clinical challenge. Here, we identify the pro-survival BCL-2 protein family member MCL-1 as a resistance factor for the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma (NHL) cell lines and primary NHL samples. Mechanistically, we show that the antibody-drug conjugate polatuzumab vedotin promotes MCL-1 degradation via the ubiquitin/proteasome system. This targeted MCL-1 antagonism, when combined with venetoclax and the anti-CD20 antibodies obinutuzumab or rituximab, results in tumor regressions in preclinical NHL models, which are sustained even off-treatment. In a Phase Ib clinical trial (NCT02611323) of heavily pre-treated patients with relapsed or refractory NHL, 25/33 (76%) patients with follicular lymphoma and 5/17 (29%) patients with diffuse large B-cell lymphoma achieved complete or partial responses with an acceptable safety profile when treated with the recommended Phase II dose of polatuzumab vedotin in combination with venetoclax and an anti-CD20 antibody.
Stimulated Raman Scattering Microscopy Enables Gleason Scoring of Prostate Core Needle Biopsy by a Convolutional Neural Network
Authors: Jianpeng Ao, Xiaoguang Shao, Zhijie Liu, Qiang Liu, Jun Xia, Yongheng Shi, Lin Qi, Jiahua Pan, Minbiao Ji
Journal: Cancer Research (2023)

Focal therapy (FT) has been proposed as an approach to eradicate clinically significant prostate cancer while preserving the normal surrounding tissues to minimize treatment-related toxicity. Rapid histology of core needle biopsies is essential to ensure the precise FT for localized lesions and to determine tumor grades. However, it is difficult to achieve both high accuracy and speed with currently available histopathology methods. Here, we demonstrated that stimulated Raman scattering (SRS) microscopy could reveal the largely heterogeneous histologic features of fresh prostatic biopsy tissues in a label-free and near real-time manner. A diagnostic convolutional neural network (CNN) built based on images from 61 patients could classify Gleason patterns of prostate cancer with an accuracy of 85.7%. An additional 22 independent cases introduced as external test dataset validated the CNN performance with 84.4% accuracy. Gleason scores of core needle biopsies from 21 cases were calculated using the deep learning SRS system and showed a 71% diagnostic consistency with grading from three pathologists. This study demonstrates the potential of a deep learning-assisted SRS platform in evaluating the tumor grade of prostate cancer, which could help simplify the diagnostic workflow and provide timely histopathology compatible with FT treatment.A platform combining stimulated Raman scattering microscopy and a convolutional neural network provides rapid histopathology and automated Gleason scoring on fresh prostate core needle biopsies without complex tissue processing.
Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial
Authors: Charles N. Landen, Luciana Molinero, Habib Hamidi, Jalid Sehouli, Austin Miller, Kathleen N. Moore, Cagatay Taskiran, Michael Bookman, Kristina Lindemann, Charles Anderson, Regina Berger, Tashanna Myers, Mario Beiner, Thomas Reid, Els Van Nieuwenhuysen, Andrew Green, Aikou Okamoto, Carol Aghajanian, Premal H. Thaker, Stephanie V. Blank, Victor K. Khor, Ching-Wei Chang, Yvonne G. Lin, Sandro Pignata
Journal: Clinical Cancer Research (2023)

Abstract Purpose: To explore whether patients with BRCA1/2-mutated or homologous recombination deficient (HRD) ovarian cancers benefitted from atezolizumab in the phase III IMagyn050 (NCT03038100) trial. Patients and Methods: Patients with newly diagnosed ovarian cancer were randomized to either atezolizumab or placebo with standard chemotherapy and bevacizumab. Programmed death-ligand 1 (PD-L1) status of tumor-infiltrating immune cells (IC) was determined centrally (VENTANA SP142 assay). Genomic alterations, including deleterious BRCA1/2 alterations, genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI), were evaluated using the FoundationOne assay. HRD was defined as gLOH ≥ 16%, regardless of BRCA1/2 mutation status. Potential associations between progression-free survival (PFS) and genomic biomarkers were evaluated using standard correlation analyses and log-rank of Kaplan–Meier estimates. Results: Among biomarker-evaluable samples, 22% (234/1,050) harbored BRCA1/2 mutations and 46% (446/980) were HRD. Median TMB was low irrespective of BRCA1/2 or HRD. Only 3% (29/1,024) had TMB ≥10 mut/Mb, and 0.3% (3/1,022) were MSI-high. PFS was better in BRCA2-mutated versus BRCA2–non-mutated tumors and in HRD versus proficient tumors. PD-L1 positivity (≥1% expression on ICs) was associated with HRD but not BRCA1/2 mutations. PFS was not improved by adding atezolizumab in BRCA2-mutated or HRD tumors; there was a trend toward enhanced PFS with atezolizumab in BRCA1-mutated tumors. Conclusions: Most ovarian tumors have low TMB despite BRCA1/2 mutations or HRD. Neither BRCA1/2 mutation nor HRD predicted enhanced benefit from atezolizumab. This is the first randomized double-blind trial in ovarian cancer demonstrating that genomic instability triggered by BRCA1/2 mutation or HRD is not associated with improved sensitivity to immune checkpoint inhibitors. See related commentary by Al-Rawi et al., p. 1645
In glucocorticoid-dependent polymyalgia rheumatica, tocilizumab improved a composite clinical outcome at 24 wk
Authors: David S. Pisetsky
Journal: Annals of Internal Medicine (2023)

Source Citation Devauchelle-Pensec V, Carvajal-Alegria G, Dernis E, et al. Effect of tocilizumab on disease activity in patients with active polymyalgia rheumatica receiving glucocorticoid therapy: a randomized clinical trial. JAMA. 2022;328:1053-62. 36125471
Physical Activity Interventions to Alleviate Depressive Symptoms in Children and Adolescents
Authors: Francesco Recchia, Joshua D. K. Bernal, Daniel Y. Fong, Stephen H. S. Wong, Pak-Kwong Chung, Derwin K. C. Chan, Catherine M. Capio, Clare C. W. Yu, Sam W. S. Wong, Cindy H. P. Sit, Ya-Jun Chen, Walter R. Thompson, Parco M. Siu
Journal: JAMA Pediatrics (2023)

Depression is the second most prevalent mental disorder among children and adolescents, yet only a small proportion seek or receive disorder-specific treatment. Physical activity interventions hold promise as an alternative or adjunctive approach to clinical treatment for depression.
IL6 Mediates Suppression of T- and NK-cell Function in EMT-associated TKI-resistant EGFR-mutant NSCLC
Authors: Sonia A. Patel, Monique B. Nilsson, Yan Yang, Xiuning Le, Hai T. Tran, Yasir Y. Elamin, Xiaoxing Yu, Fahao Zhang, Alissa Poteete, Xiaoyang Ren, Li Shen, Jing Wang, Seyed Javad Moghaddam, Tina Cascone, Michael Curran, Don L. Gibbons, John V. Heymach
Journal: Clinical Cancer Research (2023)

Patients with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are initially responsive to tyrosine kinase inhibitors (TKI). However, therapeutic resistance eventually emerges, often via secondary EGFR mutations or EGFR-independent mechanisms such as epithelial-to-mesenchymal transition. Treatment options after EGFR-TKI resistance are limited as anti-PD-1/PD-L1 inhibitors typically display minimal benefit. Given that IL6 is associated with worse outcomes in patients with NSCLC, we investigate whether IL6 in part contributes to this immunosuppressed phenotype.We utilized a syngeneic genetically engineered mouse model (GEMM) of EGFR-mutant NSCLC to investigate the effects of IL6 on the tumor microenvironment and the combined efficacy of IL6 inhibition and anti-PD-1 therapy. Corresponding in vitro studies used EGFR-mutant human cell lines and clinical specimens.We identified that EGFR-mutant tumors which have oncogene-independent acquired resistance to EGFR-TKIs were more mesenchymal and had markedly enhanced IL6 secretion. In EGFR-mutant GEMMs, IL6 depletion enhanced activation of infiltrating natural killer (NK)- and T-cell subpopulations and decreased immunosuppressive regulatory T and Th17 cell populations. Inhibition of IL6 increased NK- and T cell-mediated killing of human osimertinib-resistant EGFR-mutant NSCLC tumor cells in cell culture. IL6 blockade sensitized EGFR-mutant GEMM tumors to PD-1 inhibitors through an increase in tumor-infiltrating IFNγ+ CD8+ T cells.These data indicate that IL6 is upregulated in EGFR-mutant NSCLC tumors with acquired EGFR-TKI resistance and suppressed T- and NK-cell function. IL6 blockade enhanced antitumor immunity and efficacy of anti-PD-1 therapy warranting future clinical combinatorial investigations.
In tobacco smokers with respiratory symptoms, a dual bronchodilator did not reduce symptoms at 12 wk
Authors: Claudia C. Dobler
Journal: Annals of Internal Medicine (2023)

ACP Journal ClubJanuary 2023In tobacco smokers with respiratory symptoms, a dual bronchodilator did not reduce symptoms at 12 wkClaudia C. Dobler, MD, PhDClaudia C. Dobler, MD, PhDUniversity of New South Wales, Sydney, New South Wales, Australia (C.C.D.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/J22-0103 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationHan MK, Ye W, Wang D, et al. Bronchodilators in tobacco-exposed persons with symptoms and preserved lung function. N Engl J Med. 2022;387:1173-84. https://pubmed.ncbi.nlm.nih.gov/36066078Clinical Impact RatingsGIM/FP/GP: Pulmonology: References1. Thomas ET, Glasziou P, Dobler CC. Use of the terms “overdiagnosis” and “misdiagnosis” in the COPD literature: a rapid review. Breathe (Sheff). 2019;15:e8-e19. [PMID: 31031840] Google Scholar2. Zhou Y, Zhong NS, Li X, et al. Tiotropium in early-stage chronic obstructive pulmonary disease. N Engl J Med. 2017;377:923-35. [PMID: 28877027] Google Scholar Author, Article, and Disclosure InformationAuthors: Claudia C. Dobler, MD, PhDAffiliations: University of New South Wales, Sydney, New South Wales, Australia (C.C.D.)Disclosures: The commentator has reported no disclosures of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=J22-0103.This article was published at Annals.org on 3 January 2023.ACP Journal Club is editorially independent from Annals of Internal Medicine. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics January 2023Volume 176, Issue 1Page: JC6KeywordsBronchodilatorsChronic obstructive pulmonary diseaseDyspneaForced expiratory volume in the first second of expirationInhalationLungsPulmonary diseasesQuestionnairesRespiratory system proceduresSpirometry ePublished: 3 January 2023 Issue Published: January 2023 Copyright & PermissionsCopyright © 2023 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Paroxysmal nocturnal hemoglobinuria: Where we stand
Authors: Jens Panse
Journal: American Journal of Hematology (2023)

Abstract For the last 20 years, therapy of paroxysmal nocturnal hemoglobinuria (PNH) relied—up until recently—on antibody based terminal complement inhibitionon. PNH pathophysiology—a mutational defect leading to partial or complete absence of complement‐regulatory proteins on blood cells—leads to intravascular hemolysis and consequences such as thrombosis and other sequelae. A plethora of new drugs interfering with the proximal and terminal complement cascade are under recent development and the first “proof‐of‐pinciple” proximal complement inhibitor targeting C3 has been approved in 2021. “PNH: where we stand” will try to give a brief account on where we came from and where we stand focusing on approved therapeutic options. The associated improvements as well as potential consequences of actual and future treatments as well as their impact on the disease will continue to necessitate academic and scientific focus on improving treatment options as well as on side effects and outcomes relevant to individual patient lives and circumstances in order to develop effective, safe, and available treatment for all hemolytic PNH patients globally.
Pharmacologic Treatment of Primary Osteoporosis or Low Bone Mass to Prevent Fractures in Adults: A Living Clinical Guideline From the American College of Physicians
Authors: Amir Qaseem, Lauri A. Hicks, Itziar Etxeandia-Ikobaltzeta, Tatyana Shamliyan, Thomas G. Cooney
Journal: Annals of Internal Medicine (2023)

Description: This guideline updates the 2017 American College of Physicians (ACP) recommendations on pharmacologic treatment of primary osteoporosis or low bone mass to prevent fractures in adults. Methods: The ACP Clinical Guidelines Committee based these recommendations on an updated systematic review of evidence and graded them using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Audience and Patient Population: The audience for this guideline includes all clinicians. The patient population includes adults with primary osteoporosis or low bone mass. Recommendation 1a: ACP recommends that clinicians use bisphosphonates for initial pharmacologic treatment to reduce the risk of fractures in postmenopausal females diagnosed with primary osteoporosis (strong recommendation; high-certainty evidence). Recommendation 1b: ACP suggests that clinicians use bisphosphonates for initial pharmacologic treatment to reduce the risk of fractures in males diagnosed with primary osteoporosis (conditional recommendation; low-certainty evidence). Recommendation 2a: ACP suggests that clinicians use the RANK ligand inhibitor (denosumab) as a second-line pharmacologic treatment to reduce the risk of fractures in postmenopausal females diagnosed with primary osteoporosis who have contraindications to or experience adverse effects of bisphosphonates (conditional recommendation; moderate-certainty evidence). Recommendation 2b: ACP suggests that clinicians use the RANK ligand inhibitor (denosumab) as a second-line pharmacologic treatment to reduce the risk of fractures in males diagnosed with primary osteoporosis who have contraindications to or experience adverse effects of bisphosphonates (conditional recommendation; low-certainty evidence). Recommendation 3: ACP suggests that clinicians use the sclerostin inhibitor (romosozumab, moderate-certainty evidence) or recombinant PTH (teriparatide, low-certainty evidence), followed by a bisphosphonate, to reduce the risk of fractures only in females with primary osteoporosis with very high risk of fracture (conditional recommendation). Recommendation 4: ACP suggests that clinicians take an individualized approach regarding whether to start pharmacologic treatment with a bisphosphonate in females over the age of 65 with low bone mass (osteopenia) to reduce the risk of fractures (conditional recommendation; low-certainty evidence).
Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma
Authors: Zijian Yang, Cong Yan, Jiaqiang Ma, Panpan Peng, Xuelian Ren, Shangli Cai, Xia Shen, Yingcheng Wu, Shu Zhang, Xiaoying Wang, Shuangjian Qiu, Jian Zhou, Jia Fan, He Huang, Qiang Gao
Journal: Nature Metabolism (2023)
Tic Status in Tourette Syndrome Due to Depletion of the Deep Brain Stimulation Battery
Authors: Jacy Bezerra Parmera, Joyce Yuri Silvestre Yamamoto, Rubens Gisbert Cury
Journal: JAMA Neurology (2023)

In this case report, a patient with Tourette syndrome was admitted to the emergency department with nonrhythmic, continuous, generalized hyperkinetic movements associated with muscle contractions in the trunk, neck, and upper and lower limbs caused by depletion of the deep brain stimulation battery.
Elarekibep (PRS-060/AZD1402), a new class of inhaled Anticalin medicine targeting IL-4Ra for type 2 endotype asthma
Authors: Gabriele Matschiner, Mary F Fitzgerald, Ulrich Moebius, Andreas M Hohlbaum, Hendrik Gille, Kristian Jensen, Klaus Kirchfeld, Barbara Rattenstetter, Alice Laforge, Rachida S Bel Aiba, Joe Ciccotosto, Hong Nyugen, Martyn L Foster, John N Snouwaert, MyTrang Nguyen, Beverly H Koller, Louis Matis, Gary P Anderson, Shane A Olwill
Journal: Journal of Allergy and Clinical Immunology (2022)